Dr. Wertheim's career goal is to become an independent investigator and physician-scientist in liver tissue engineering to advance the fields of transplantation and tissue engineered organs. He has demonstrated a continued commitment to this objective through his undergraduate training at MIT with Prof. Robert Langer, graduate research in cell adhesion at the Univ. of Pennsylvania and surgical training at the Massachusetts General Hospital and UCLA Medical Center. Together, Dr. Wertheim's training as a transplant surgeon and scientific background in biomedical engineering provide a strong foundation for his proposed research in liver tissue engineering. Now at Northwestern University, his role is to develop a research program in liver tissue engineering, and he has unwavering support from his Department and mentors. Dr. Wertheim's immediate goal is to use the protected research time and mentorship structure of the K08 Award to enhance his knowledge and scientific research skills in liver pathobiology to effectively study hepatocellular function and response to 3D matrix environments with the eventual goal of developing a tissues engineered organ for therapeutic transplantation. Despite the development of protease inhibitors to treat Hepatitis C, liver disease will continue to be a major public health problem in the foreseeable future due to the obesity epidemic in the US leading to metabolic syndrome, nonalcoholic steatohepatitis (NASH), hypertension and diabetes. The increased incidence of obesity, and associated diseases, will not just increases the need for transplantable bioartificial livers, but other organs as well. Dr. Wertheim's lab has developed Small bioArtificial, Micro-sized Scaffolds (SAMS) that are made from an acellular rat liver scaffold. This environment allows the interaction of hepatocytes with extracellular matrix molecules, growth factors, and other cells to be studied in a controlled manner. His lab has also developed innovative flow bioreactors that are perfusion culture systems where hepatocytes grow within whole-organ 3D liver matrices derived from decellularized rodent tissue. The goals of this proposal are to advance upon preliminary data indicating that the extracellular matrix in SAMS enhances the activity of hepatocytes developed using induced pluripotent stem cell technology (iPS- hepatocytes). The Aims are 1) To evaluate the influence of stellate cells, which regulate extracellular matrix remodeling, on the functioning of iPS-hepatocytes in SAMS and 2) To combine SAMS with novel signaling peptides that are more efficient than full-length matrix molecules, to further enhance iPS-hepatocyte function. The scientific environment at Northwestern, the mentorship team and career development plan have been created around Dr. Wertheim's objective to use protected time to enrich his knowledge and understanding of hepatocyte pathophysiology and nanotechnology to help close the gap created by surgical training. Dr. Janaradan Reddy is Dr. Wertheim's primary mentor and an experienced physician-scientist in the Department of Pathology at Northwestern. Dr. Reddy's laboratory has particular expertise in hepatocyte progenitor cell biology, cell isolation, development of animal models with liver-specific abnormalities and a particular focus on hepatotoxin-mediated hepatocarcinogenesis. Dr. Richard Green is the Chief of the Section of Hepatology at Northwestern. His research specializes in the molecular pathogenesis of hepatic bile salt metabolism. Dr. Samuel Stupp is a world-renowned researcher in nanotechnology. He is the Director of the Institute for BioNanotechnology in Medicine (IBNAM) at Northwestern, of which Dr. Wertheim is a member. Dr. Stupp is a world leader in nanotechnology and his research continues to advance the field of biofunctional peptides. Dr. Michael Abecassis is the Chief of the Division of Transplantation at Northwestern, the Founding Director of the Comprehensive Transplant Center, and was the 7th highest ranked surgeon funded by the NIH in 2011. This proposal leverages the strength of Northwestern's training programs, Centers and Institutes to enhance Dr. Wertheim's career development and apply knowledge of hepatocyte biology to his liver tissue engineering research. The Comprehensive Transplant Center will be Dr. Wertheim's center of gravity with seminars in hepatology, liver pathology and mentors in scientific research at all levels. Dr. Wertheim is a member of IBNAM that is a collaborative, multidisciplinary institute with state-of-the art facilities including peptide sequencing for development of biofunctional peptides and 3D bioprinting. Dr. Wertheim is also a member of the Chemistry of Life Processes (CLP) Institute at Northwestern. CLP fosters transdisciplinary collaboration among physical and life scientists to address the complexity of big questions. CLP facilities specialize in high throughput robotic analysis of small molecular compounds and sophisticated imaging resources that span length scales from molecules to whole animals. This proposal, and the assembled environmental and mentoring structure, addresses dual, but complementary purposes: 1) To advance Dr. Wertheim's scientific skills in the physiology of liver pathobiology through a structured mentorship and protected scientific framework and 2) To use stellate cells and cutting- edge biofunctional peptides to evaluate critical cell-matrix and cell-cell relationshis in a tissue engineered liver scaffold. These objectives, and the unwavering support of the University, will provide Dr. Wertheim with the skills necessary to attain his goal to become an independent, surgeon-scientist in liver tissue engineering.